Process for O-acylating phenol derivatives and acylating compositions for this purpose

ABSTRACT

A process is disclosed for preparing a carbamic acid phenyl ester of the formula (I) ##STR1## wherein R is alkyl having 1 to 8 carbon atoms, aryl, cycloalkyl having 5 or 6 carbon atoms, or aralkyl having 7 to 16 carbon atoms, wherein the aryl, cycloalkyl or aralkyl is unsubstituted or substituted by at least one alkyl group having 1 to 8 carbon atoms; 
     R 1  is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyanomethyl, 1,3-dioxolan-2-yl, or carboalkoxyamino wherein the alkoxy group contains 1 to 4 carbon atoms; 
     R 2  is hydrogen, halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms; or 
     R 1  and R 2  form together a carbocyclic ring or a heterocyclic ring fused to the phenyl ring wherein the carbocyclic ring of the heterocyclic ring is unsubstituted or substituted by at least one alkyl having 1 to 8 carbon atoms, which comprises acylating a phenol of the formula (II) ##STR2##  with a compound of the formula (IV) ##STR3##  in the presence of a base. The compounds obtained are valuable intermediates.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of copending Ser. NO. 201,508filed Oct. 28, 1980.

The invention relates to a new process for O-acylating phenolderivatives and to acylating compositions suitable for this purpose.More particularly, the invention concerns a new process for thepreparation of substituted carbamic acid phenyl ester derivatives of theformula (I) ##STR4## by O-acylating phenols of the formula (II) ##STR5##

In the above formulae and throughout the specification

R is alkyl having 1 to 8 carbon atoms, aryl, cycloalkyl having 5 or 6carbon atoms, or aralkyl having 7 to 16 carbon atoms, wherein the aryl,cycloalkyl or aralkyl is unsubstituted or substituted by at least onealkyl group having 1 to 8 carbon atoms;

R₁ is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4carbon atoms, cyanomethyl, 1,3-dioxolan-2-yl, or carboalkoxyaminowherein the alkoxy group contains 1 to 4 carbon atoms;

R₂ is hydrogen, halogen, alkyl having 1 to 4 carbon atoms or alkoxyhaving 1 to 4 carbon atoms; or

R₁ and R₂ form together a carbocyclic ring or a heterocyclic ring fusedto the phenyl ring wherein the carbocyclic ring or the heterocyclic ringis unsubstituted or substituted by at least one alkyl having 1 to 8carbon atoms.

Compounds of the formula (I) are generally used for protecting plantsfrom plant diseases.

In the specification aryl preferably means phenyl or naphthyl. The termaralkyl preferably means benzyl or phenethyl. The term carbocyclic ringincludes any saturated or unsaturated homocyclic ring system. Preferablya cyclopentyl, cyclohexyl or cycloheptyl ring is contemplated. The termheterocyclic ring may include any heterocyclic ring system containing atleast one oxygen, sulfur or nitrogen heteroatom. Preferably theheterocyclic ring system includes a pyran or furan ring which may behydrogenated.

Representative compounds of the formula II include2,3-dihydro-2,2-dimethyl-benzofuran-7-ol, a C₁ to C₄alkyl-(N-3-hydroxyphenyl)-carbamate or 2-(1,3-dioxolan-2-yl)phenol.

A well-known process for the preparation of compounds of the formula(I), wherein R¹, R² and R are as hereinabove defined, consists in theaddition of phenol derivatives of the formula (II), wherein R¹ and R²are as defined above, to isocyanates of the formula (III)

    R--N═C═O                                           (III)

Due to the toxicity and mucous membrane irritating properties of theisocyanates, this process can, however, be carried out only under verystrict labor-safety regulations, and therefore its performance is rathercumbersome. A further disadvantage is derived from the stronglyexothermic character of the isocyanate addition reaction, which involvesfurther technological problems, especially when isocyanates with a lowboiling point are used, and may also lead to undesired side reactions.Moreover, certain isocyanates can be stored and tranported only underspecial conditions, which involves further expenses and theiraccessability is restricted.

An alternative possibility for the preparation of compounds of theformula (I) consists of the reaction of compounds of the formula (II)with monosubstituted carbamic acid chlorides. The monosubstitutedcarbamic acid chlorides are, however, unstable compounds (unlike theirdisubstituted analogues) and are easily transformed into isocyanateswhile hydrochloric acid is split off. These unstable compounds can beprepared also by the addition reaction of isocyanate and hydrochloricacid. It would, however, not be expected that a nucleophilic agent (forexample a compound of the formula (II)) can be acylated withoutsplitting off hydrochloric acid. Moreover, the disadvantages listed inthe preceding paragraph are to be faced increasingly when carrying outthis process.

Compounds of the formula (I) can also be prepared by reacting compoundsof the formula (II) with phosgene and acylating an amine of the formulaR--NH₂ by the chloroformic acid ester derivative obtained. This processis, however, due to the extreme toxicity of phosgene gas, highlydisadvantageous.

It has now been found that carbamic acid phenyl ester derivatives of theformula (I) can be prepared with an excellent yield, in high purity byO-acylating phenols of the formula (II). According to this processphenols of the formula (II) are reacted with N-carbamoyl-saccharinderivatives of the formula (IV) ##STR6## in the presence of a base.

As bases inorganic bases, preferably alkali metal hydroxides,carbonates, hydrocarbonates; alkali earth metal hydroxides, carbonates,hydrocarbonates; and tertiary amines, preferably triethyl amine can beused. The base is expediently used at least in an amount equivalent tothe acylating agent of the formula (IV).

The reaction of the compounds of the formula (II) with the compounds ofthe formula (IV) is preferably carried out in an organic solvent, or ina mixture of an organic solvent and water. As organic solventshydrocarbons, lower ketones or esters (acetone, methylethyl ketone,ethyl acetate), ethers (dioxane, tetrahydrofurane), chlorinated solvents(chloroform, dichloroethane), lower acid amides (formamide, dimethylformamide) can for example be employed. It is preferred to use solventsin which at least two of the starting compounds (including the base) issoluble, and the compound of the formula (I) obtained is insoluble, oris dissolved but can be precipitated without accompanying impurities.When an inorganic base is used, the reaction product if desired, can bepurified also by treating with water. The organic bases are morepreferred, taking into account also the solubility of the salt-likeadducts prepared therefrom in organic solvents, especially in solventsystems, in which the compound of the formula (I) obtained is insolublewhile the organic base and its saccharin adduct are soluble.

The compounds of the formula (II) are reacted with the compounds of theformula (IV) at 0° to 100° C., preferably at room temperature,expediently under stirring. The compounds obtained are preferablyisolated by crystallization or precipitation with a suitable solvent,while saccharin which is split off during the reaction remains in thesolution as a salt formed with the base employed. From this saltsaccharin can easily be isolated and can repeatedly be used for thepreparation of an acylating agent of the formula (IV).

While according to the methods known in the art compounds of the formula(I) could be prepared only by an addition or a two-step substitutionreaction, according to the invention these compounds are obtained by aone-step substitution reaction. Accordingly, the compounds of theformula (I) can be prepared in an aqueous medium.

A further advantage of the process according to the invention consistsin the fact that no toxic, gaseous or liquid acylating agents are used.The N-carbamoyl-saccharin derivatives are crystalline solids, which areeasy to handle and can unrestrictedly be stored. Since the acylationcarried out by using these agents is far less exothermic than forexample acylation performed with isocyanates, the undesiredside-reactions can be avoided and compounds of the formula (I) can beprepared in high purity, with excellent yield.

According to a further feature of the invention there is provided anacylating composition suitable for acylating phenolic hydroxyls, whichcontains 5 to 50% by weight of a compound of the formula (IV), wherein Ris hereinbefore defined, in admixture with 0.20 to 30% by weight of butat least an equivalent amount of the base and 10 to 80% by weight of asolvent.

The preferred acylating compositions contain as an acylating agentN-phenyl-carbamoyl-benzoic acid sulfinide, N-methyl-carbamoyl-benzoicacid sulfinide, N-butyl-carbamoyl-benzoic acid sulfinide,N-(3-methylphenyl)-carbamoyl-benzoic acid sulfinide, in admixture withtriethyl amine as a base and acetone as a solvent.

Further details of our invention are illustrated by the followingExamples. It is, however, by no means intended to limit our invention tothe Examples.

EXAMPLE 1

4.3 g (0.025 moles) of methyl-(N-3-hydroxyphenyl)-carbamate are reactedwith 7.3 g (0.025 moles) of N-phenylcarbamoylbenzoic acid sulfimide(m.p.: 184°-186° C.) in 15 ml of acetone, in the presence of 2.56 g(0.025 moles) of triethyl amine, at 40° C. for 15 minutes. To thereaction mixture 40 ml of water are added and it is cooled to 5° to 10°C. The mixture is allowed to stand for 30 minutes, filtered, washed anddried. 5.5 g of 3-methoxycarbonylaminophenyl-phenyl carbamate areobtained, melting at 150° to 152° C.

Benzoic acid imide can be precipitated from the mother liquor byhydrochloric acid.

EXAMPLE 2

3.35 g (0.025 moles) of 2,3-dihydro-2,2-dimethyl-benzofuran-7-ol arereacted with 6 g (0.025 moles) of N-methylcarbamoyl-benzoic acidsulfimide in 15 ml of acetone, in the presence of 2.56 g (0.025 moles)of triethyl amine, at 50° C. for 15 minutes. The reaction mixture isthen cooled to room temperature, diluted with 100 ml of water; theprecipitate is filtered off, washed with water and dried. 3.1 g of2,3-dihydro-2,2-dimethyl-benzofurane-7-yl methyl-carbamate are obtained,melting at 150° to 152° C. Benzoic acid sulfimide can be recovered byprecipitation from the mother liquor with an acid.

EXAMPLE 3

1.5 g of N-methylcarbamoyl-benzoic acid sulfimide are suspended in amixture of 1 g of 2,3-dihydro-2,2-dimethylbenzofurane-7-ol in 5 ml ofacetone and 5 ml of water, where upon a solution of 0.6 g of triethylamine in a mixture of 2 ml of acetone and 1 ml of water is addeddropwise in 30 minutes, and the mixture is stirred for an additional 1.5hours. The precipitated crystals are filtered off, washed with water anddried. 0.745 g of 2,3-dihydro-2,2-dimethylbenzofurane-7-ylmethylcarbamate are obtained, melting at 150° to 152° C.

EXAMPLE 4

4.3 g of (0.025 moles) of methyl-(N-3-hydroxyphenyl)-carbamate arerefluxed with 7.3 g (0.025 moles) of N-phenyl-carbamoyl-benzoic acidsulfimide (m.p.: 184° to 186° C.) in 15 ml of acetone, in the presenceof 2 g (0.0145 moles) of potassium carbonate for 15 minutes. 40 ml ofwater are then added and the mixture is cooled to 5° to 10° C. Afterstanding for 1 hour, the precipitated crystals are filtered off, washedand dried. 5.8 g of 3-methoxycarbonylaminophenyl-phenylcarbamate areobtained, melting at 150° to 152° C.

EXAMPLE 5

4.5 g of (0.025 moles) of ethyl-(N-3-hydroxyphenyl)-carbamate arereacted with 7.3 g (0.025 moles) of N-phenyl-carbamoyl-benzoic acidsulfimide in 15 ml of acetone, in the presence of 2.56 g (0.025 moles)of triethyl amine at 40° C. for 15 minutes. Upon addition of 40 ml ofwater the reaction mixture is cooled to 5° C., allowed to stand for 30minutes, filtered, washed and dried. 5.7 g of3-ethoxycarbonyl-aminophenyl-phenylcarbamate are obtained, melting at117° to 119° C.

EXAMPLE 6

4.2 g (0.025 moles) of methyl-(N-3-hydroxyphenyl)-carbamate are reactedwith 7.9 g (0.025 moles) of N-(3-methylphenyl)-carbamoyl-benzoic acidsulfimide in 15 ml of acetone, in the presence of 2.56 g (0.025 moles)of triethyl amine at 30° C. for 30 minutes. Upon addition of 50 ml ofwater the reaction mixture is cooled to 5° to 10° C., allowed to standfor 30 minutes, filtered, washed and dried. 5.3 g of3-methoxycarbamoylphenyl-3'-methylphenyl-carbamate are obtained, meltingat 140° to 142° C.

By precipitation with hydrochloric acid 3.5 g (76%) of benzoic acidsulfimide are recovered. This method can equally be employed in any ofthe preceding examples.

EXAMPLE 7

5 g. of N-methyl-carbamoyl-benzoic acid sulfimide are suspended in amixture of 2.67 g. of 2-Chlorophenol and 50 g of acetone. The mixture isthen cooled to 5° C., and while stirring a solution of 2.9 mltriethylamine in 30 ml acetone is added dropwise. The temperature of themixture during addition (two hours) was not allowed to increase above 6°C. After standing for 12 hours and stirring at a temperature of 5° C.240 ml of distilled water were added in portions to the mixture thenextracted with 3×30 ml of ether. The ethereal extracts were dried withsodium sulfate, then the solvent was evaporated in a vacuum at atemperature not above 30° C.

3.13 g of 2-chlorophenyl N-methyl-carbamate are obtained afterrecrystallization from N-pentane, melting at 90°-91° C.

EXAMPLE 8

5 g of N-methyl-carbamoyl-benzoic acid sulfimide are suspended in amixture of 2.6 g of 2-methoxyphenol and 50 ml acetone and while stirringat room temperature, a solution of 2.9 ml triethylamine in 30 ml acetonewas added dropwise, in an hour. The mixture is stirred for an additional2 hours at room temperature, then 240 ml of distilled water are slowlyadded to the mixture and extracted with 3×30 ml of ether. The etherealextract is dried with sodium sulfate, the solvent is evaporated in avacuum at a temperature not above 30° C. 2.43 g of 2-methoxy-phenylN-methyl-carbamate are obtained, recrystallized from N-pentane, meltingat 90°-92° C.

EXAMPLE 9

2.4 g of N-methyl-carbamoyl-benzoic acid sulfimide are suspended in amixture of 1.63 g of 2-methoxy-4-cyanomethyl-phenol in 15 ml of acetone,and while stirring at room temperature, a solution of 1.4 ml oftriethylamine in 5 ml of acetone is added, in an hour. After standinganother 2 hours at room temperature, 65 ml of distilled water are addedto the mixture. After standing for 15 hours at 5° C., the precipitatedcrystals are filtered off, washed with water and dried. 0.72 g ofproduct are obtained, melting at 138°-139° C.

Analysis: Calculated: C--O/O; 59.99, H--O/O; 5.45, N--O/O; 12.72. Found:C--O/O; 60.05, J--O/O; 5.52, N--O/O; 12.65.

The remaining liquid after the crystallization is washed with 3×10 ml ofether, the ethereal extracts are dried with sodium sulfate, then areplace in vacuum at a temperature not above 30° C. The solvent isevaporated and an additional 0.95 g of I-methoxy-4-cyanomethyl-phenylN-methyl-carbamate are obtained.

EXAMPLE 10

5 g N-butyl-carbamic acid benzoic acid sulfimide are suspended in themixture of 1.67 g of phenol and 50 ml of water, then while stirring (5hours), a solution of 0.71 g of sodium hydroxide in 50 ml water isadded. After stirring another 3 hours, the mixture is extracted with2×30 ml of ether. The ethereal extracts are dried with sodium sulfate,then the solvent is evaporated in a vacuum at a temperature not above30° C. 2.15 g of phenyl N-butyl-carbamate are obtained, which can bedistilled at 146°-148° C. at 2 mmHg.

EXAMPLE 11

5 g N-tertiary butyl-carbamoyl-benzoic acid sulfimide and 1.9 g of4-methyl-phenol in 50 ml chloroform are heated to the boiling point,then while stirring, a mixture of 2.5 ml of triethylamine and 30 ml ofchloroform is added, in an hour. After boiling an hour the solvent isevaporated in a vacuum, the oily residue mixed with ether. Theprecipitated benzoic acid sulfimide triethyl amine salt is filteredthen, the ethereal solution is evaporated in vacuum at a temperature notabove 30° C.

2.4 g of 4-methyl-phenyl N-tertiary butyl carbamate is obtained, meltingat 130°-132° C., after crystallized from petrolether.

What is claimed is:
 1. A process for preparing a carbamic acid phenylester of the formula (I) ##STR7## wherein R is alkyl having 1 to 8carbon atoms, aryl, cycloalkyl having 5 or 6 carbon atoms, or aralkylhaving 7 to 16 carbon atoms, wherein the aryl, cycloalkyl, or aralkyl isunsubstituted or substituted by at least one alkyl group having 1 to 8carbon atoms; R₁ is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxyhaving 1 to 4 carbon atoms, cyanomethyl, 1,3-dioxolan-2-yl, orcarboalkoxyamino wherein the alkoxy group contains 1 to 4 carbonatoms;R₂ is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, oralkoxy having 1 to 4 carbon atoms; or R₁ and R₂ form together acarbocyclic ring or a heterocyclic ring fused to the phenyl ring whereinthe carbocyclic ring or heterocyclic ring is unsubstituted orsubstituted by at least one alkyl having 1 to 8 carbon atoms, whichcomprises acylating a phenol of the formula (II) ##STR8## with acompound of the formula (IV) ##STR9## in the presence of a base.
 2. Aprocess as claimed in claim 1, which comprises carrying out theacylation in the presence of at least one molar equivalent of a base. 3.A process as claimed in claim 2, which comprises using inorganic bases,preferably alkali metal hydroxides, carbonates, hydrocarbonates; alkaliearth metal hydroxides, carbonates, hydrocarbonates, or tertiary aminebases, preferably triethyl amine.
 4. A process as claimed in claim 1which comprises carrying out the reaction of the compound of the formula(II) with the compound of the formula (IV) in an organic solvent, in amixture of an organic solvent and water or in water.
 5. A process asclaimed in claim 1 which comprises carrying out the reaction of thecompound of the formula (II) with the compound of the formula (IV) at atemperature of 0° to 100° C., preferably at room temperature.
 6. Aprocess as claimed in claim 1, which comprises using2,3-dihydro-2,2-dimethyl-benzofuran-7-ol, a C₁ to C₄alkyl-(N-3-hydroxyphenyl)-carbamate or 2-(1,3-dioxolan-2-yl)-phenol asthe phenol.